Inhibition of colony-stimulating-factor-1 signaling<i>in vivo</i>with the orally bioavailable cFMS kinase inhibitor GW2580

Conway, James G.; McDonald, Brad; Parham, Janet H.; Keith, Barry R.; Rusnak, David W.; Shaw, Eva; Jansen, Marilyn; Lin, Psang Dain; Payne, Alan; Crosby, Renae M.; Johnson, Jennifer H.; Frick, Lloyd; Lin, Min-Hwa Jasmine; Depee, Scott; Tadepalli, Sarva M.; Votta, Bart; James, Ian E.; Fuller, K.; Chambers, T.J.; Kull, Frederick C.; Chamberlain, Stanley D.; Hutchins, Jeff

doi:10.1073/pnas.0502000102

Cited by 215 publications

(239 citation statements)

References 42 publications

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“…As shown in Table 3, all three compounds dose dependently inhibited M-NFS-60 cell proliferation in the intraperitoneal (IP) cavity of mice when dosed orally. 31 Maximal effect was observed at 100 mg/kg for 18b and at 30 mg/kg for 22a and 22b, consistent with the exposure difference among them.…”

Section: Acs Medicinal Chemistry Letterssupporting

confidence: 75%

Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases

Liu¹,

Campbell²,

Holladay³

et al. 2012

ACS Med. Chem. Lett.

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A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collageninduced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate. KEYWORDS: platelet-derived growth factor receptor (PDGFR)-family kinases, feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3), colony-stimulating factor-1 receptor (CSF1R) inhibitor, acute myeloid leukemia (AML), cancer bone metastasis, inflammatory arthritis, AC710 R eceptor tyrosine kinases (RTKs) are a subfamily of protein kinases that critically regulate the processes of normal cell signaling and many pathological conditions. 1 A class of RTKs known as the platelet-derived growth factor receptor (PDGFR) family, 2,3 which includes colony-stimulating factor-1 receptor (CSF1R, also known as FMS), feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3), stem cell factor receptor (KIT), and PDGFR α and β, has been implicated in various proliferative and inflammatory diseases. 4 We were particularly interested in two members of this family of kinases. Activating internal tandem duplication (ITD) mutations in FLT3 are detected in approximately 30% of acute myeloid leukemia (AML) patients and are associated with poor prognosis. 5 AC220 (1, quizartinib) (Figure 1), a potent FLT3 inhibitor from this laboratory, 6 has demonstrated convincing clinical activity in FLT3-ITD+ AML patients. 7 CSF1R is the exclusive receptor for the macrophage colonystimulating factor (M-CSF or CSF-1). 8 Activation of CSF1R leads to the proliferation, survival, motility, and differentiation of cells of the monocyte/macrophage lineage and hence plays a role in normal tissue development and immune defense. 9,10 Activation of CSF1R also leads to the proliferation and differentiation of osteoclast precursors and therefore mediates the process of bone resorption. 11 It has been shown that M-CSF is one of several cytokines implicated in the recruitment of tumor-associated macrophages (TAMs) that contribute to tumor angiogenesis and tumor progression to metastasis. 12 More recently, the preclinical CSF1R inhibitor GW2580 (2) (Figure 1) inhibited tumor metastasis and angiogenesis in mouse tumor xenograft experiments. 13 JNJ-28312141 (3), a dual inhibitor of CSF1R and FLT3, also demonstrated suppression of solid tumor growth and preservation of bone in preclinical models. 14 CSF1R is also implicated in inflammatory arthritis, as M-CSF, together with RANK ligand, is required for osteoclastogenesis. 15 Elevated M-CFS signaling leads to increased osteoclast activity and bone loss attending arthritis, 16 a...

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Section: Acs Medicinal Chemistry Letterssupporting

confidence: 75%

Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases

Liu¹,

Campbell²,

Holladay³

et al. 2012

ACS Med. Chem. Lett.

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“…We asked if active Akt could rescue the mitogenic defect of DKI cells. The E40K mutation in the pleckstrin homology domain enhances the affinity for PIP 3 while retaining growth factor inducibility. 28 DKI cells were retrovirally transduced with pMSCV-IRES-GFP vectors encoding WT-Akt, E40K-Akt or a kinase-dead (K179M) Akt, and GFP-positive mass populations isolated by cell sorting.…”

Section: Csf-1-dependent Mitogenesis Requires Both Erk and Pi3-kinasementioning

confidence: 99%

“…2 Recently, a CSF-1R kinase inhibitor has been developed to target macrophages in disease states such as arthritis, osteoporosis and cancer. 3 For these reasons, it is essential to understand how CSF-1 supports the proliferation and survival of myeloid lineage cells.…”

Section: Introductionmentioning

confidence: 99%

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Lee

States

2006

Cell Death Differ

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Colony-stimulating factor-1 (CSF-1) is essential for macrophage growth, differentiation and survival. Myeloid cells expressing a CSF-1 receptor mutant (DKI) show markedly impaired CSF-1-mediated proliferation and survival, accompanied by absent signal transducers and activators of transcription 3 (Stat3) phosphorylation and reduced PI3-kinase/Akt activity. Restoring phosphatidylinositol 3-kinase (PI3-kinase) but not Stat3 signals reverses the mitogenic defect. CSF-1-induced proliferation and survival are sensitive to glycolytic inhibitors, 2-deoxyglucose and 3-bromopyruvate. Consistent with a critical role for PI3-kinase-regulated glycolysis, DKI cells reconstituted with active PI3-kinase or Akt are hypersensitive to these inhibitors. CSF-1 upregulates hexokinase II (HKII) expression through PI3-kinase, and PI3-kinase transcriptionally activates the HKII promoter. Moreover, HKII overexpression partially restores mitogenicity. In contrast, Bcl-x L expression does not enhance long-term proliferation, although short-term cell death is suppressed in a glycolysis-independent manner. This study identifies robust PI3-kinase activation as essential for optimal CSF-1-mediated mitogenesis in myeloid cells, in part through regulation of HKII and support of glycolysis.

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“…For the kinase inhibitors, mice were treated by oral gavage with 160 mg/kg of GW2580 or vehicle. This dose has been shown previously to be optimal for inhibition of CSF-1R (36,37). CYC11645 is another potent inhibitor of CSF-1R (38), described previously by Burns and colleagues as compound 15 (38).…”

Section: Antibody and Inhibitor Treatmentmentioning

confidence: 99%

The Promotion of Breast Cancer Metastasis Caused by Inhibition of CSF-1R/CSF-1 Signaling Is Blocked by Targeting the G-CSF Receptor

Swierczak

Cook

Lenzo

et al. 2014

Cancer Immunology Research

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Treatment options are limited for patients with breast cancer presenting with metastatic disease. Targeting of tumor-associated macrophages through the inhibition of colony-stimulating factor-1 receptor (CSF-1R), a key macrophage signaling pathway, has been reported to reduce tumor growth and metastasis, and these treatments are now in clinical trials. Here, we report that, surprisingly, treatment with neutralizing anti-CSF-1R and anti-CSF-1 antibodies, or with two different small-molecule inhibitors of CSF-1R, could actually increase spontaneous metastasis without altering primary tumor growth in mice bearing two independently derived mammary tumors. The blockade of CSF-1R or CSF-1 led to increased levels of serum G-CSF, increased frequency of neutrophils in the primary tumor and in the metastasis-associated lung, as well as increased numbers of neutrophils and Ly6C hi monocytes in the peripheral blood. Neutralizing antibody against the G-CSF receptor, which regulates neutrophil development and function, reduced the enhanced metastasis and neutrophil numbers that resulted from CSF-1R blockade. These results indicate that the role of the CSF-1R/CSF-1 system in breast cancer is far more complex than originally proposed, and requires further investigation as a therapeutic target. Cancer Immunol Res; 2(8); 765-76. Ó2014 AACR.

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Inhibition of colony-stimulating-factor-1 signalingin vivowith the orally bioavailable cFMS kinase inhibitor GW2580

Cited by 215 publications

References 42 publications

Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases

Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

The Promotion of Breast Cancer Metastasis Caused by Inhibition of CSF-1R/CSF-1 Signaling Is Blocked by Targeting the G-CSF Receptor

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